Weizmann Institute of Science scientists revealed the discovery and outlined a path for future treatment
Acute liver failure is a fatal medical condition; Without an urgent liver transplant, 80% of cases end in death. In developed countries, the main cause of this is excessive use of high doses of the well-known pain reliever acetaminophen.
Recently, Weizmann Institute of Science scientists discovered three new subtypes of liver cells that play a key role in the development of acute liver failure in mice. in the study, the published in the scientific journal Nature Medicine, the scientists from the laboratories of Prof. Eran Alinev and Prof. Ido colleague in the department of immunology, that signals originating from the intestinal bacteria and the liver activate these cells, and that blocking the signals and eliminating the intestinal bacteria significantly improve liver function and survival in mice. Examining the liver tissues of patients with acute liver failure revealed a molecular pattern similar to that in mice - a finding that raises hope about the possibility of translating the findings into human treatment.
Dr. Alexandra Kolodzika, a post-doctoral researcher in Prof. Alinev's laboratory, led the project in collaboration with other scientists from the institute and with Dr. Amir Shlomai from the National Institute of Liver Diseases at the Rabin Medical Center (Bilinson). Dr. Kolodzica and her colleagues first mapped the gene expression in 45 thousand liver cells of healthy mice and mice with acute liver failure and identified 49 subtypes of cells - including three new subtypes of stellate cells, endothelial cells and Kupffer cells that are activated in a manner Abnormal during acute liver failure. These subtypes secreted a variety of substances that attracted cells of the immune system to the liver and thereby contributed to the destruction of the vital organ. All three subtypes were characterized by a certain expression pattern of 77 genes, which are controlled by the same control protein - the transcription factor MYC; These findings indicated that the cells are activated using the same genetic activation software.
The scientists hypothesized that it is possible that signals originating from the intestinal bacteria affect the activation software they discovered, since the intestines drain into the liver through a branching network of veins, thereby exposing the liver to substances originating from the intestines and their bacteria. As hypothesized, when the gut bacteria in the mice were eliminated with antibiotics, the symptoms of insufficiency improved. Furthermore, when the scientists created acute liver failure in mice lacking gut bacteria, the disease was much less severe than in normal mice. Additional studies in mice revealed that in acute liver failure, molecules secreted by intestinal bacteria accumulate in the liver and activate the MYC protein there in the three subtypes discovered; Without the gut bacteria, MYC is less activated, resulting in less liver damage.
Later, Dr. Kolodzika deciphered the molecular details of MYC activation: she found that molecules originating from intestinal bacteria activate MYC through receptors on the surface of the three subtypes identified as contributing to liver failure. She also found that MYC is activated in the same way by signals coming from the liver cells themselves after they have been damaged by acetaminophen.
When the scientists eliminated active receptors of this type in mice or gave them drugs that blocked MYC itself or interfered with the communication between MYC and the receptors, the mice did not develop acute liver failure and their survival improved. The examination of gene expression showed that in the mice that received the treatments, the three new subtypes of the liver cells were not activated abnormally as before, therefore the movement of the cells of the immune system to the liver was also reduced and the damage to its tissue was significantly reduced.
Finally, the scientists teamed up with Dr. Shlomai to examine liver samples from patients with acute liver failure and healthy liver donors. The samples from the patients - but not from healthy donors - were characterized by a strong activation of MYC similar to the observation in mice. These findings raise the possibility that blocking MYC and its activation pathways with drugs, along with an effect on the gut bacteria, may be a treatment for acute liver failure.
Prof. Alinev says: "The findings are a first step towards a comprehensive understanding of how the interactions between the human body and its intestinal bacteria contribute to acute liver failure. This understanding may lead to new treatments for this dangerous and incurable medical condition."
Dr. Sara Federici, Dr. Niv Zamora, Dr. Gayatra Mohapatra, Dr. Meli Bakhsh, Shani Hornstein, Dr. Avner Leshem and Dr. Hagit Shapira from Prof. Alinev's laboratory participated in the study; Dr. Tomer Meir Selma from the Department of Life Science Research Infrastructures of the Institute; Prof. Alon Hermlin from the veterinary resources department of the institute; Dr. Debi Reuvani and Dr. Ehud Sigmund from the Sourasky Tel Aviv Medical Center; And Dr. Anna Tober from the Rabin Medical Center.
